Adult: In patients who would normally be maintained on oral Na valproate and for whom oral treatment is temporarily not possible: As Na valproate: For patients already satisfactorily treated with Na valproate therapy: Continue at the current dosage using continuous or repeated IV infusion. For other patients: Usual dose of 400-800 mg depending on the body weight (up to 10 mg/kg) may be given via slow IV inj over 3-5 minutes, followed by continuous or repeated infusion up to a Max of 2,500 mg daily. Switch to oral Na valproate therapy as soon as possible. Dosage recommendations may vary among individual products or between countries (refer to detailed product guidelines). Elderly: As Na valproate: Initiate at lower doses and increase slowly. Child: As Na valproate: Usual dose range: 20-30 mg/kg daily via slow IV inj over 3-5 minutes or via continuous or repeated infusion. If adequate control is not attained, doses may be increased up to 40 mg/kg daily (only in patients whose plasma valproic acid levels may be monitored).
Oral Acute manic episodes of bipolar disorder
Adult: As valproate semisodium: Initially, 750 mg daily in 2-3 divided doses (as delayed-release tab), or initial dose of 25 mg/kg once daily (as extended-release tab). Thereafter, increase the dose as rapidly as possible to attain the lowest therapeutic dose that produces the desired clinical effect or range of plasma concentrations. Max: 60 mg/kg daily. Carefully monitor patients receiving doses >45 mg/kg daily. Dosage recommendations may vary among individual products or between countries (refer to detailed product guidelines). Elderly: As valproate semisodium: Initiate at lower doses and increase slowly.
Adult: Monotherapy or adjunctive therapy: As valproic acid or valproate semisodium: Initially, 15 mg/kg daily, then increased by 5-10 mg/kg at weekly intervals until seizures are controlled. Max: 60 mg/kg daily. Administer in divided doses if the total daily dose exceeds 250 mg. Elderly: As valproic acid or valproate semisodium: Initiate at lower doses and increase slowly.
Oral Prophylaxis of migraine
Adult: As valproate semisodium: As extended-release tab: Initially, 500 mg once daily for 1 week, then increased to 1,000 mg once daily. As delayed-release tab: Initially, 250 mg bid. Doses up to 1,000 mg may be given in certain patients. Dosage must be individualised and adjusted according to response. Elderly: As valproate semisodium: Initiate at lower doses and increase slowly.
Oral Complex partial seizures
Adult: Monotherapy or adjunctive therapy for the treatment of cases that occur either alone or in association with other seizure types: As valproic acid or valproate semisodium: Initially, 10-15 mg/kg daily, then increased by 5-10 mg/kg at weekly intervals to achieve optimal clinical response. Doses may be given in 2-4 divided doses. Max: 60 mg/kg daily. As Na valproate: Initially, 600 mg daily in 2 divided doses, then increased by 200 mg every 3 days until control is attained. Usual dose range: 1,000-2,000 mg daily (20-30 mg/kg daily). If adequate control is not attained, dose may be further increased up to 2,500 mg daily. Dosage recommendations may vary among individual products or between countries (refer to detailed product guidelines). Elderly: As valproic acid, valproate semisodium, or Na valproate: Initiate at lower doses and increase slowly. Child: Monotherapy or adjunctive therapy for the treatment of cases that occur either alone or in association with other seizure types: As Na valproate: Children weighing <20 kg: Initially, 20 mg/kg daily in 2 divided doses. In severe cases, doses may be increased only if plasma valproic acid levels can be monitored; children weighing >20 kg: Initially, 400 mg daily (regardless of weight) in 2 divided doses; may be gradually increased until control is attained. Usual dose range: 20-30 mg/kg daily. If adequate control is not attained, dose may be further increased to 35 mg/kg daily. As valproic acid or valproate semisodium: ≥10 years Same as adult dose. Dosage recommendations may vary among individual products or between countries (refer to detailed product guidelines).
Special Patient Group
Mutations in the mitochondrial DNA polymerase γ (POLG) gene may cause hereditary neurometabolic syndromes such as Alpers-Huttenlocher syndrome. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. There is an increased risk of valproate-induced acute liver failure and liver-related deaths in patients with these hereditary neurometabolic syndromes, particularly in children and adolescents. To identify individuals who are at high risk of developing valproate-induced hepatotoxicity, POLG mutation testing should be performed in accordance with the current clinical practice.
Renal Impairment
Dosage adjustment may be needed.
Hepatic Impairment
Contraindicated.
Administration
Should be taken with food.
Reconstitution
IV: Reconstitute a vial containing 400 mg with the solvent provided (4 mL of sterile water for inj). Due to the displacement of solvent by Na valproate, the reconstituted Na valproate concentration is 95 mg/mL. Further dilute the appropriate dose with 0.9% NaCl solution, 5% dextrose in water, or Lactated Ringer’s inj. Instructions for reconstitution and compatible diluents may vary among countries and individual products. Refer to specific product guidelines.
Contraindications
Known mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG) such as Alpers-Huttenlocher syndrome; known urea cycle disorders, porphyria, personal or family history of severe hepatic dysfunction. Hepatic impairment. Children <2 years of age who are clinically suspected of having a POLG-related disorder. Pregnancy and women of childbearing potential who are not using effective contraception (when used for prophylaxis of migraine).
Special Precautions
Patient with SLE, carnitine palmitoyltransferase (CPT) type II deficiency; risk factors for hepatotoxicity (e.g. children <3 years of age, those on multiple anticonvulsant agents, those with severe seizure disorders, organic brain disease, congenital metabolic or degenerative disease associated with mental retardation). Patients undergoing surgery. Use valproic acid in patients >2 years who are clinically suspected of having hereditary mitochondrial disease only after other anticonvulsant agents have failed. Medication residue in the stool may occur rarely in patients taking oral valproate semisodium. Refer to specific product guidelines when switching between different brands or formulations. Avoid abrupt withdrawal. Not recommended for the treatment of dementia-associated agitation or aggression, and post-traumatic seizure prophylaxis in patients with acute head trauma. Children and elderly. When used for epilepsy and bipolar disorder, valproic acid must not be used in pregnant women, those planning to become pregnant, and women of childbearing potential unless other agents failed to provide adequate symptom control or are otherwise unacceptable. Lactation.
Adverse Reactions
Significant: Suicidal ideation and behaviour, CNS effects (e.g. dizziness, drowsiness, nervousness, insomnia, tremor, delirium, hallucinations, parkinsonism, cognitive dysfunction); thrombocytopenia (dose-related), acquired von Willebrand disease type I, haemorrhage, haemorrhagic stroke; hyperammonaemia (may be present despite normal LFTs), hypothermia; delayed hypersensitivity reactions (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome [SJS]); porphyria, increased liver enzymes, weight gain; reversible worsening of convulsion frequency and severity, new-onset of other types of convulsions; rhabdomyolysis (specifically in patients with CPT type II deficiency); major congenital malformation, particularly neural tube defects (e.g. spina bifida). Blood and lymphatic system disorders: Anaemia, pancytopenia, leucopenia. Ear and labyrinth disorders: Tinnitus, deafness (reversible or irreversible). Endocrine disorders: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH), hyperandrogenism (e.g. hirsutism, acne). Eye disorders: Nystagmus. Rarely, diplopia. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, gingival hyperplasia, stomatitis, gastralgia, dyspepsia, abdominal pain, flatulence. General disorders and administration site conditions: Asthenia, peripheral oedema. IV: Inj site reactions (e.g. pain, inflammation). Investigations: Decreased bone mineral density. Immune system disorders: Hypersensitivity. Metabolism and nutrition disorders: Hyponatraemia, anorexia. Musculoskeletal and connective tissue disorders: Osteopenia, osteoporosis, fractures (prolonged use). Nervous system disorders: Headache, extrapyramidal disorder, encephalopathy, memory impairment. Psychiatric disorders: Aggression, agitation, attention disturbance, confusional state, stupor. Renal and urinary disorders: Urinary incontinence. Reproductive system and breast disorders: Dysmenorrhoea, amenorrhoea. Very rarely, gynaecomastia. Respiratory, thoracic and mediastinal disorders: Pharyngitis, rhinitis, bronchitis, dyspnoea. Skin and subcutaneous tissue disorders: Transient or dose-related alopecia, nail and nail bed disorders, ecchymosis. Potentially Fatal: Serious hepatotoxicity, including hepatic failure; hyperammonemic encephalopathy, pancreatitis or haemorrhagic pancreatitis that progresses rapidly from initial symptoms; drug reaction with eosinophilia and systemic symptoms (DRESS).
IV/Parenteral/PO: Z (Congenital, developmental and pregnancy-related adverse events have been reported. Not recommended or contraindicated. Consult prescribing or clinical guidelines for specific recommendations.); PO: Z (Congenital, developmental and pregnancy-related adverse events have been reported. Not recommended or contraindicated. Consult prescribing or clinical guidelines for specific recommendations.)
Patient Counseling Information
This drug may cause transient drowsiness, if affected, do not drive or operate machinery. Women of childbearing potential must use highly effective birth control methods without interruption during therapy.
Monitoring Parameters
Pregnancy test may be considered in women of childbearing potential to rule out pregnancy before initiating treatment. Perform POLG mutation testing in accordance with the current clinical practice for the diagnosis of such disorders. Monitor serum valproate levels as clinically indicated; LFTs (at baseline and frequently thereafter, particularly during the 1st 6 months of therapy), CBC with platelets (at baseline and periodically), prothrombin time/partial thromboplastin time (prior to therapy initiation and especially before surgery), and serum ammonia (with mental status changes). Check for mental alertness; evidence of haemorrhage, bruising, or a disorder of haemostasis/coagulation; menstrual history to assess for polycystic ovary syndrome (at 3-6 monthly intervals for the 1st year, and annually thereafter). Closely assess for signs and symptoms of hepatotoxicity (particularly in patients >2 years who are suspected of having a hereditary mitochondrial disease), pancreatitis, suicidal ideation, behavioural changes, depression, decline in motor and cognitive function, and DRESS.
Overdosage
Symptoms: Nausea, vomiting, dizziness, somnolence, heart block, intracranial hypertension associated with cerebral oedema, muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis, hypotension, circulatory collapse/shock, seizures, CNS depression, and deep coma. Management: Symptomatic and supportive treatment. Establish airway and breathing and perform cardiorespiratory monitoring. May give activated charcoal within 1-2 hours after ingestion. May perform gastric lavage within 10-12 hours following ingestion. IV Naloxone, sometimes given with activated charcoal, may be administered to reverse CNS depressant effects (use cautiously in patients with epilepsy). Ensure adequate urinary output. Respiratory depression may require assisted mechanical ventilation. May perform haemodialysis or tandem haemodialysis and haemoperfusion.
Drug Interactions
Increased risk of liver toxicity with salicylates. May enhance the effects of other psychotropic agents (e.g. antipsychotics, MAO inhibitors, antidepressants, benzodiazepines). Increased plasma concentrations of phenobarbital and primidone leading to sedation. May decrease the plasma concentrations of phenytoin and olanzapine. May potentiate the toxic effects of carbamazepine. May reduce the metabolism and increase the half-life of lamotrigine resulting in an increased risk of SJS and toxic epidermal necrolysis. May decrease the plasma protein binding and increase the anticoagulant effects of warfarin and other coumarin anticoagulants. Increased valproic acid plasma concentration with felbamate, aspirin, cimetidine, erythromycin, and chlorpromazine. Increased valproic acid metabolism causing a lower seizure threshold with mefloquine and chloroquine. Increased risk of hyperammonaemia (with or without encephalopathy) with topiramate and acetazolamide. Valproic acid plasma concentrations may be decreased with enzyme-inducing antiepileptics (e.g. phenytoin, phenobarbital, carbamazepine), carbapenem antibiotics (e.g. meropenem, imipenem), protease inhibitors (e.g. ritonavir, lopinavir), colestyramine, rifampicin, and metamizole. Estrogen-containing hormonal contraceptives may increase valproate clearance which may result in decreased valproate serum concentration and potentially reduced valproate efficacy. May increase the plasma levels of rufinamide, nimodipine, propofol, and zidovudine. May increase the risk of neutropenia/leucopenia with quetiapine.
Food Interaction
Food may delay the rate but not the extent of absorption. May potentiate the CNS depressant effect of alcohol.
Lab Interference
May affect thyroid function test results. May cause false-positive results for test of urine ketones.
Action
Description: Mechanism of Action: Valproate is a general term used to describe valproic acid, its salts and derivatives. Valproic acid is a carboxylic acid, Na valproate is the Na salt of valproic acid, and valproate semisodium is a stable coordination compound composed of valproic acid and Na valproate in a 1:1 molar relationship. Valproic acid and its salt forms (Na valproate, valproate semisodium) are anticonvulsant agents that dissociate in the gastrointestinal tract to form valproate ions. The mechanism by which valproate exerts its effects have not been established, but it has been suggested that its antiepileptic activity is related to increased brain concentrations of GABA.
Synonym: As valproate semisodium: divalproex Na. Pharmacokinetics: Absorption: Rapidly and completely absorbed from the gastrointestinal tract. Delayed rate but not the extent of absorption with food. Bioavailability: Approx 90% relative to IV dose and approx 89% relative to delayed-release formulation (extended-release formulation). Time to peak plasma concentration: As valproate semisodium: Approx 4 hours (delayed-release tab and sprinkle cap); 3-5 hours (gastro-resistant tab); 4-17 hours (extended-release). Distribution: Crosses the placenta; enters breast milk (small amounts). Distributed into the CSF. Volume of distribution: 11 L/1.73 m2 (total valproate); 92 L/1.73 m2 (free valproate). Plasma protein binding (concentration-dependent): 80-90%; free-fraction increases from approx 10% at approx 40 mcg/mL to 18.5% at approx 130 mcg/mL. Metabolism: Extensively metabolised in the liver mainly via glucuronide conjugation and mitochondrial β-oxidation; undergoes other oxidative metabolic pathways to a lesser extent. Excretion: Via urine (30-50% as glucuronide conjugate, <3% as unchanged drug); faeces and expired air (small amounts). Elimination half-life: 5-20 hours.
Chemical Structure
Valproic acid Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3121, Valproic acid. https://pubchem.ncbi.nlm.nih.gov/compound/Valproic-acid. Accessed Oct. 26, 2022.
Storage
Conventional tab or cap, extended-release or delayed-release tab: Store between 15-30°C. Controlled-release or modified-release granules, sprinkle cap, crushable tab, gastro-resistant tab, or prolonged-release tab: Store below 30°C. Protect from moisture. Oral solution or syr: Store below 25°C. Protect from light. Solution for inj or infusion: Store below 30°C. Diluted solution for infusion: Stable between 2-8°C for up to 24 hours. Storage recommendations may vary among individual products and between countries. Refer to specific product guidelines.
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